Treatment Of Early Stage Non-small Cell Lung Cancer Research Articles

Abstract 986: Mathematical modeling of ctDNA dynamics to predict utility of ultrasensitive MRD assays in early stage non-small cell lung cancer (NSCLC)

Abstract Background: ctDNA assay use for minimal residual disease (MRD) detection in early stage NSCLC has been limited by suboptimal sensitivity of first generation assays. It is unclear how improving assay limit of detection (LOD) would translate to improvements in clinical sensitivity. Here, we performed mathematical modeling of ctDNA dynamics after curative-intent treatment in early stage NSCLC to predict the clinical impact of MRD assays with improved analytical sensitivity. Methods: We analyzed a recently reported dataset of post-surgical ctDNA MRD surveillance in early stage NSCLC (Abbosh et al., Nature 2023) to investigate ctDNA growth dynamics. Of 70 relapsed patients in this cohort, 23 had 3 consecutive ctDNA-positive samples with no intervening therapy. We used these to generate patient-specific mathematical models for ctDNA variant allele fractions (VAF) over time, initially assuming exponential growth. We assessed this assumption by creating log-linear models for ctDNA increase in these cases. Using slopes of the log-linear models, we calculated patient-specific doubling times and assessed their relation to stage, histology, and outcome. We used the log-linear models to simulate a VAF distribution each day after surgery, enabling projection of clinical sensitivities and estimation of lead times for recurrence detection at varying LODs. Results: For the 23 cases with 3+ consecutive ctDNA positive samples, we developed log-linear models for ctDNA VAF growth, which were strongly correlated (r > 0.5) in 18/23 (78%) patients (median r = 0.89), supporting that ctDNA can be modeled as exponential growth. We calculated ctDNA doubling times for the 18 patients with exponential ctDNA kinetics and 10 patients with 2 consecutive ctDNA positive samples. Doubling times were remarkably consistent with median 51 days (IQR 40-79). Doubling times were longer for stage I tumors compared to stage II/III (p = 0.04) but were not different between NSCLC subtypes. Doubling time correlated with time to clinical relapse, with patients having more rapid ctDNA growth relapsing earlier (r = 0.52, p=0.03). Finally, we used patient-specific log-linear models to project ctDNA VAFs at a landmark 30 days after surgery. By improving the LOD for ctDNA detection from 10−4 to 10−6, the projected clinical sensitivity doubled (from 43% to 86%). Simulations predicted that this improvement in sensitivity would increase median lead time from 183 days for LOD=10−4 to 349 days for LOD=10−6 (p<0.0001). Conclusion: For most relapsed NSCLC patients, the natural history of ctDNA MRD growth can be reliably modeled with exponential growth kinetics. ctDNA doubling time is associated with stage and clinical outcome. Ultrasensitive MRD assays with LOD of 10−6 are predicted to meaningfully improve clinical sensitivity at the post-surgical landmark and to increase the lead time for MRD detection before relapse. Citation Format: Jordan S. Goldstein, Christopher Abbosh, Ash A. Alizadeh, Maximilian Diehn, David M. Kurtz. Mathematical modeling of ctDNA dynamics to predict utility of ultrasensitive MRD assays in early stage non-small cell lung cancer (NSCLC) [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2024; Part 1 (Regular Abstracts); 2024 Apr 5-10; San Diego, CA. Philadelphia (PA): AACR; Cancer Res 2024;84(6_Suppl):Abstract nr 986.

Comparison of postoperative complications in mediastinal lymph node dissection versus mediastinal lymph node sampling for early stage non-small cell lung cancer: Protocol for a systematic review and meta-analysis.

Lung cancer is the primary cause of cancer-related deaths worldwide, with high rates of morbidity and mortality. The most effective treatment for early stage (I-II) non-small cell lung cancer (NSCLC) is surgical resection. However, the extent of mediastinal lymph nodes removal required and the impact of their removal remains controversial. This systematic review and meta-analysis aimed to evaluate the postoperative complications in patients with stage I-II NSCLC who received mediastinal lymph node dissection (MLND) or mediastinal lymph node sampling (MLNS). According to the predefined inclusion criteria, we will conduct a comprehensive search for randomized controlled trials (RCTs) and observational studies examining the postoperative complications of MLND compared to MLNS in patients with stage I-II NSCLC. The search will be performed across multiple databases including PubMed, Embase, the Cochrane Library, CNKI, WanFang, Sinomed, VIP, Duxiu, and Web of Science from inception to February 2024. Additionally, relevant literature references will be retrieved and hand searching of pertinent journals will be conducted. Screening, data extraction, and quality assessment will be performed by two independent reviewers. Review Manager 5.4 will be applied in analyzing and synthesizing. The Grading of Recommendations Assessment, Development and Evaluation (GRADE) will be used to assess the quality of evidence for the whole RCTs and used Newcastle-Ottawa scale to assess the methodologic quality of observational studies. This study did not include personal information. Ethical approval was not required for this study. This study is based on a secondary analysis of the literature, so ethical review approval is not required. The final report will be published in a peer-reviewed journal. This systematic review will contribute to compare the safety and survival benefits of these two surgical techniques for the treatment of early stage NSCLC, to further guide the selection of surgical approaches. The protocol of the systematic review has been registered on Open Science Framework, with a registration number of DOI https://doi.org/10.17605/OSF.IO/N2Y5D.

Multicentric development and evaluation of [18F]FDG PET/CT and CT radiomic models to predict regional and/or distant recurrence in early-stage non-small cell lung cancer treated by stereotactic body radiation therapy.

To develop machine learning models to predict regional and/or distant recurrence in patients with early-stage non-small cell lung cancer (ES-NSCLC) after stereotactic body radiation therapy (SBRT) using [18F]FDG PET/CT and CT radiomics combined with clinical and dosimetric parameters. We retrospectively collected 464 patients (60% for training and 40% for testing) from University Hospital of Liège and 63 patients from University Hospital of Brest (external testing set) with ES-NSCLC treated with SBRT between 2010 and 2020 and who had undergone pretreatment [18F]FDG PET/CT and planning CT. Radiomic features were extracted using the PyRadiomics toolbox®. The ComBat harmonization method was applied to reduce the batch effect between centers. Clinical, radiomic, and combined models were trained and tested using a neural network approach to predict regional and/or distant recurrence. In the training (n = 273) and testing sets (n = 191 and n = 63), the clinical model achieved moderate performances to predict regional and/or distant recurrence with C-statistics from 0.53 to 0.59 (95% CI, 0.41, 0.67). The radiomic (original_firstorder_Entropy, original_gldm_LowGrayLevelEmphasis and original_glcm_DifferenceAverage) model achieved higher predictive ability in the training set and kept the same performance in the testing sets, with C-statistics from 0.70 to 0.78 (95% CI, 0.63, 0.88) while the combined model performs moderately well with C-statistics from 0.50 to 0.62 (95% CI, 0.37, 0.69). Radiomic features extracted from pre-SBRT analog and digital [18F]FDG PET/CT outperform clinical parameters in the prediction of regional and/or distant recurrence and to discuss an adjuvant systemic treatment in ES-NSCLC. Prospective validation of our models should now be carried out.

Perioperative immunotherapy in stage IB-III non-small cell lung cancer: a critical review of its rationale and considerations.

Lung cancer is a dismal disease as a leading cause of overall cancer death, but the development of immune checkpoint inhibitors (ICIs) in driver gene mutation negative metastatic non-small cell lung cancer (NSCLC) is changing the paradigm of lung cancer treatment. Recently, ICIs are expanding their treatment area to early-stage NSCLC and ICIs have also changed their treatment strategies of such patients. And it is important to appropriately select patients with resectable early-stage lung cancer through a multidisciplinary team approach and decrease the tumor relapse rate in the ICIs era. In this review article, we discuss the recently released neoadjuvant and adjuvant data of ICIs, their treatment rationale, and unmet needs in the treatment of early-stage NSCLC.

Pre-existing tumor host immunity characterization in resected non-small cell lung cancer

IntroductionNeoadjuvant and adjuvant immune checkpoint blockade (ICB) have recently become standard of care in resectable non-small cell lung cancer (NSCLC). Yet, biomarkers that inform patients who benefit from this approach remain largely unknown. Here, we interrogated the tumor immune microenvironment (TIME) in early-stage NSCLC patients that underwent up-front surgery. MethodsA total of 185 treatment-naïve patients with early-stage NSCLC, that underwent up-front surgical treatment between 2006 and 2018 at Hospital del Mar were included. 124 lung adenocarcinomas (LUADs), and 61 squamous cell carcinoma (LUSCs) were included in a tissue microarray. Immunohistochemistry for CD3, CD4, CD8, CD68, CD80, CD103, FOXP3, PD-1, PD-L1, PD-L2 and HLA class II were evaluated by digital image analysis (QuPath software). TIME was categorized into four groups using PD-L1 expression in tumor cells (<1 % or ≥1 %) and tumor resident memory (CD103+) immune cells (using the median as cut-off). We explored the association between different TIME dimensions and patient’s clinicopathological features and outcomes. ResultsWe found increased levels of T cell markers (CD3+, CD4+, CD8+ cells), functional immune markers (FOXP3+ cells) as well as, higher HLA-II tumor membrane expression in LUADs compared to LUSCs (p < 0.05 for all). In contrast, LUSCs displayed higher percentage of intratumor macrophages (CD68+ cells) as well as, higher PD-L1 and PD-L2 tumor membrane expression (p < 0.05 for all). Unsupervised analysis revealed three different tumor subsets characterized by membrane tumor expression of PD-L1, PD-L2 and HLA-class II. Enrichment of T cells (CD3+, CD8+ cells), regulatory T cells (FOXP3+ cells) and macrophages (CD68+ cells) was observed in the CD103+/PD-L1+ group (p < 0.05 for all). Multivariate analysis showed that infiltration by CD103+ immune cells was associated with improved OS (p = 0.009). ConclusionsTIME analysis in resected NSCLC highlighted differences by histology, PD-L1 expression and molecular subgroups. Biomarker studies using IHC might aid to individually tailor adjuvant treatment in early-stage NSCLC.

Role of Neoadjuvant Immune Checkpoint Inhibitors in Resectable Non-Small Cell Lung Cancer.

The neoadjuvant use of immune checkpoint inhibitors (ICI) in resectable non-small cell lung cancer (NSCLC) is being increasingly adopted, but questions about the most appropriate applications remain. Although patients with resectable NSCLC are often treated with surgery and adjuvant chemotherapy or targeted therapies +/- radiotherapy, they still have a high risk of recurrence and death. In recent years, immune checkpoint inhibitors (ICI) (anti-PD-1/PD-L1 and anti-CTLA-4) have provided a new and effective therapeutic strategy for the treatment of advanced NSCLC. Therefore, it is possible that ICIs for early-stage NSCLC may follow the pattern established in metastatic disease. Currently, there are several ongoing trials to determine the efficacy in the neoadjuvant setting for patients with local or regional disease. To date, only nivolumab in combination with chemotherapy has been approved by the U.S. FDA in the preoperative setting, but data continue to evolve rapidly, and treatment guidelines need to be determined. In this article, we review the current preclinical and clinical evidence on neoadjuvant ICIs alone and combination in the treatment of early-stage NSCLC.

EP04.01-002 Costs of Locoregional and Metastatic Recurrences in Patients with Resectable Stage II-III NSCLC in Spain

The Spanish Society of Medical Oncology (SEOM) estimates 30,948 new lung cancer cases in Spain for 2022, and around 85% of lung cancers are non-small cell lung cancer (NSCLC). More than half of patients with resecable stage II-III NSCLC experience disease recurrence within 5 years of treatment, so the economic burden of relapse is expected to be high. The objective of this analysis was to estimate the cost of disease recurrence (both locoregional and metastatic) after appropriate treatment of early-stage NSCLC (eNSCLC) in Spain.

Relationship between Dose Prescription Methods and Local Control Rate in Stereotactic Body Radiotherapy for Early Stage Non-Small-Cell Lung Cancer: Systematic Review and Meta-Analysis.

Simple SummaryStereotactic body radiotherapy (SBRT) is a standard treatment for inoperable early stage non-small-cell lung cancer (ES-NSCLC), and good local control and low toxicity rates have been reported. However, the optimal dose prescription method remains unclear. Variations in dose prescription methods make it difficult to properly compare the outcomes of SBRT for ES-NSCLC with those of previously published studies. Therefore, in this study, we conducted a comprehensive search of the published literature on the therapeutic results of SBRT for ES-NSCLC to summarize the results and clarify the relationship between LC and dose prescription methods. In our results, the central biologically effective dose of the planning target volume was most correlated with 3-year local control rates. A comparison against a standardized central biologically effective dose would show more definite outcomes of SBRT for ES-NSCLC and would help to strengthen its use in the treatment for ES-NSCLC.Variations in dose prescription methods in stereotactic body radiotherapy (SBRT) for early stage non-small-cell lung cancer (ES-NSCLC) make it difficult to properly compare the outcomes of published studies. We conducted a comprehensive search of the published literature to summarize the outcomes by discerning the relationship between local control (LC) and dose prescription sites. We systematically searched PubMed to identify observational studies reporting LC after SBRT for peripheral ES-NSCLC. The correlations between LC and four types of biologically effective doses (BED) were evaluated, which were calculated from nominal, central, and peripheral prescription points and, from those, the average BED. To evaluate information on SBRT for peripheral ES-NSCLC, 188 studies were analyzed. The number of relevant articles increased over time. The use of an inhomogeneity correction was mentioned in less than half of the articles, even among the most recent. To evaluate the relationship between the four BEDs and LC, 33 studies were analyzed. Univariate meta-regression revealed that only the central BED significantly correlated with the 3-year LC of SBRT for ES-NSCLC (p = 0.03). As a limitation, tumor volume, which might affect the results of this study, could not be considered due to a lack of data. In conclusion, the central dose prescription is appropriate for evaluating the correlation between the dose and LC of SBRT for ES-NSCLC. The standardization of SBRT dose prescriptions is desirable.

Abstract 1116: Spatial distribution of granzyme B to improve the predictive power of response to immunotherapy in operable lung cancer

Abstract Purpose Non-small cell lung cancer (NSCLC) accounts for about 85% of all lung cancers. There is a strong rationale for incorporating immunotherapy into the treatment of early-stage NSCLC, given the breakthrough results with PD-1 checkpoint inhibitors in advanced-stage NSCLC. How immunotherapy should be implemented in patients who are operable is still unclear. Most of the efforts so far to identify clinically useful biomarkers do not preserve spatial information and leave us blind to the critical source of information revealed in the cell-to-cell biology of the tumor microenvironment (TME). In order to overcome these limitations, we used spatial biomarkers assays that preserve this critical information about which cells are influencing treatment response. Method Frozen sections from retrospectively collected surgically resected NSCLC (adenocarcinoma and squamous cell carcinoma) tumors treated with adjuvant pembrolizumab therapy were used. Patients were classified in two groups according to their Objective Response Rate (ORR): Complete Response (CR) and Progression Disease (PD) for spatial transcriptomic and proteomics assays. Associated to RNA In situ hybridization (ISH) technology, the NanoString GeoMx™ Digital Spatial Profiling (DSP) technology was used to determine immune markers within compartment specific defined by fluorescence localization [tumor (panCK) and leucocytes (CD45)]. Wilcoxon, Linear Mixed Model and Mann-Whitney U statistic tests were used to evaluate differences between ORR groups. Results Using the spatial analysis, we identified 4 protein markers from immune cell profiling and immune activation status modules independently associated with benefit from single-agent PD-1 checkpoint blockade in spatial context. High expression of CD4, CD40, Granzyme B and HLA-DR were significantly associated with all favorable clinical outcome, whereas upregulation of extracellular matrix (ECM) proteins related to pro-tumoral reprogramming of the stroma were associated with immunotherapy resistance. We also validated the DSP finding that high granzyme level in the stroma compartment was predictive for response to check point inhibitor in the same set of patients using ISH immunofluorescence, strengthening this marker relevance in antitumor immunity and as a predictive biomarker candidate for immunotherapy in NSCLC. Conclusion This work identifies a number of relevant spatial candidate predictors of immunotherapy outcome in spatial context for operable lung cancer that show promise for future validation in larger independent cohorts. Citation Format: Corinne Ramos, Ophelie Lemieux, Adele Ponzoni, Jonathan Stauber. Spatial distribution of granzyme B to improve the predictive power of response to immunotherapy in operable lung cancer [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2022; 2022 Apr 8-13. Philadelphia (PA): AACR; Cancer Res 2022;82(12_Suppl):Abstract nr 1116.

Deconstructing ADAURA. It is Not Yet Time to Forgo Platinum-based Adjuvant Chemotherapy in Resected Early Stage (IB-IIIA) EGFR-mutant NSCLC.

Recently, the ADAURA study demonstrated statistically significant improved disease-free survival (DFS) with adjuvant osimertinib in patients with resected stage IB-IIIA non-small cell lung cancer (NSCLC) harboring an epidermal growth factor receptor (EGFR) mutation. A consistent improvement in disease-free survival (DFS) was shown, regardless of whether or not patients received adjuvant chemotherapy. Given benefit seen with and without adjuvant chemotherapy, some clinicians may be tempted to forgo chemotherapy and only offer osimertinib post surgical resection. Would this approach be appropriate? Here we carefully dissect data from the ADAURA trial and review how this may fit into the existing evidence on the treatment of early stage NSCLC by discussing five themes, the study design of ADAURA, attempts on adjuvant tyrosine kinase inhibitors, prior studies to support adjuvant chemotherapy, how adjuvant chemotherapy was administered in ADAURA and consideration of toxicities.

Initial treatment of early-stage small-sized non-small cell lung cancer for octogenarians: a population-based study.

The objectives of this study is to figure out the appropriate initial treatment and criteria for clinical decision for early-stage small-sized non-small cell lung cancer (NSCLC) among octogenarians. Elderly patients (≥80years) with stage I NSCLC (<3cm) were identified between 2004 and 2015 in the Surveillance, Epidemiology, and End Results database. Patients were divided into four cohorts regarding treatment modalities, and overall survival and cancer-specific survival were evaluated via Kaplan-Meier analysis and Cox proportional hazard model. The propensity score matching method was introduced in the subgroup analysis stratified by four clinical characteristics to identify the preferable treatment. A total of 7861 patients were included with a median overall survival of 43months (range 1-155months). In younger patients (80-85years), lobectomy was superior in improving the survival (versus segmentectomy, HR = 0.68, 95%CI 0.55-0.84; versus wedge resection, HR = 0.77; 95%CI 0.67-0.88). While in those over 85years, lobectomy was superior to wedge resection (HR = 0.72; 95%CI 0.53-0.98), and all other treatments were comparable. As stratified by T stage in those over 85years, lobectomy was superior to wedge resection (P = 0.023) for T1 disease, and the four treatments were all comparable in overall survival for T2 disease. In conclusions, the favored treatment of early stage NSCLC for octogenarians may be evaluated by age and T stage. Lobectomy might be preferred in patients between 80 and 85years whenever possible. Among those over 85years, radiotherapy might lead to a comparable prognosis and could be recommended as the prior treatment, while should surgery be recommended, lobectomy might be preferred for T1 disease and wedge resection for T2 disease.

Comparison of stereotactic body radiotherapy and radiofrequency ablation for early-stage non-small cell lung cancer: a systematic review and meta-analysis.

BackgroundStereotactic body radiation therapy (SBRT) and radiofrequency ablation (RFA) are recommended for patients with inoperable early-stage non-small cell lung cancer (NSCLC), with both offering promising results. However, it is largely unknown which of these two treatment modalities provides superior benefits for patients. Therefore, this systematic review and meta-analysis compared clinical outcomes and safety between SBRT and RFA in patients with inoperable early-stage NSCLC.MethodsEligible studies published between 2001 and 2020 were obtained through a comprehensive search of the PubMed, Medline, Embase, and Cochrane Library databases. Original English-language studies on the treatment of early-stage NSCLC with SBRT or RFA were included. Local control (LC) rates, overall survival (OS) rates, and adverse events were obtained by pooled analyses.ResultsEighty-seven SBRT studies (12,811 patients) and 18 RFA studies (1,535 patients) met the eligibility criteria. For SBRT, the LC rates (with 95% confidence intervals) at 1, 2, 3, and 5 years were 98% (97–98%), 95% (95–96%), 92% (91–93%), and 92% (91–93%), respectively, which were significantly higher than those for RFA [75% (69–82%), 31% (22–39%), 67% (58–76%), and 41% (30–52%), respectively] (P<0.01). There were no significant differences in short-term OS between SBRT and RFA [1-year OS rate: 87% (86–88%) versus 89% (88–91%), P=0.07; 2-year OS rate: 71% (69–72%) versus 69% (64–74%), P=0.42]. Regarding long-term OS, the 3- and 5-year OS rates for SBRT were 58% (56–59%) and 39% (37–40%), respectively, which were significantly (P<0.01) superior to those for RFA [48% (45–51%) and 21% (19–23%), respectively]. The most common complication of SBRT was radiation pneumonitis (grade ≥2), making up 9.1% of patients treated with SBRT, while pneumothorax was the most common complication of RFA, making up 27.2% of patients treated with RFA.DiscussionCompared with RFA, SBRT has superior LC and long-term OS rates but similar short-term OS rates. Prospective randomized trials with large sample sizes comparing the efficacy of SBRT and RFA are warranted.

Racial and socioeconomic disparities in the use of stereotactic body radiotherapy for treating non-small cell lung cancer: a narrative review.

In the past two decades, there has been a steady increase in the use of stereotactic body radiotherapy (SBRT) as an alternative to surgical intervention for early-stage non-small cell lung cancer (NSCLC) patients; however, not much is known about the impact of race and socioeconomic status (SES) on the delivery of SBRT. Here, we conduct a narrative review to examine potential disparities in the use of SBRT. Keyword searches of MEDLINE/PubMed, Web of Science, Embase, and Google Scholar databases were performed for studies focused on race, SES, and the use of SBRT published between 2000 and 2020. Six studies were identified, and showed that minority patients, especially Blacks, were less likely to receive SBRT and had a significantly longer median time between diagnosis to SBRT treatment. Patients with lower income or lower education, as well as those from lower socioeconomic regions were less likely to receive SBRT; they were more likely to receive conventionally fractionated external beam radiation (CFRT) or no treatment. These racial and socioeconomic factors were associated with worse survival in other general early-stage NSCLC studies. In conclusion, the limited number of published studies suggest significant disparities in the treatment of early-stage NSCLC with SBRT. These factors potentially lead to worse survival outcomes among vulnerable patient populations. Equal access to SBRT should be a focus of healthcare delivery systems, to ensure optimal clinical outcomes for patients with early-stage NSCLC.

The impact of stereotactic body radiation therapy on the overall survival of patients diagnosed with early-stage non-small cell lung cancer

Background and purposeStereotactic Body Radiotherapy (SBRT) has emerged as a standard treatment for inoperable early-stage non-small cell lung cancer (NSCLC) with remarkable local control. However, it is not clear if this local control translates to overall survival (OS). The objective of this study is to investigate the impact of SBRT on the OS of early-stage NSCLC patients and examine if the extent of this impact changes with the era of diagnosis, T stage, age, and comorbidity status. Materials and methodsUsing the National Cancer Database, we compared the OS of cT1–3 cN0 cM0 NSCLC patients with SBRT or observation. Multivariable analyses were adjusted for age, race, sex, income, education, place of living, hospital type, insurance status, comorbidity score, histology types, and diagnosis year. ResultsAmong 50,819 patients, 27,027 (53.18%) received SBRT and 23,792 (46.82%) were observed. Multivariable Cox Proportional-Hazards analysis demonstrated SBRT was associated with an improved OS compared to observation (HR:0.56, p < 0.001). Subset multivariable Cox Proportional-Hazards analyses stratified by T stage, year of diagnosis, age, or Charlson Score revealed that HRs of SBRT vs. observation decrease from cT1 to cT3 (0.73–0.68), from 2004 to 2015 (0.65–0.51), from <50 to ≥80 years old (1.04–0.58) and from a Charlson Score 0 to 2 (0.69–0.58). ConclusionSBRT was associated with improved OS compared to no treatment in early-stage NSCLC. The magnitude of the impact of SBRT on OS increases in patients with advanced age, higher T stages, higher comorbidity scores and more recent treatment eras.

Abstract 735: Sensitive detection of ctDNA in early stage non-small cell lung cancer patients with a personalized sequencing assay

Abstract Introduction Identification of minimal residual disease (MRD) following curative intervention of localized non-small cell lung cancer (NSCLC) holds promise for identifying patients who are at higher risk of relapse and who would benefit from adjuvant treatment. Current routine clinical practice involves serial radiographic imaging following surgery to detect macroscopic disease. Liquid biopsy can identify patients who have MRD without macroscopic disease. Currently available assays have only identified circulating tumor DNA (ctDNA) in a limited number of cases with early stage NSCLC. More sensitive methods are needed to accurately identify the majority of patients who will relapse. Here we evaluate the performance of InVision®MRD, a personalized sequencing assay for plasma cell-free DNA, for detection of ctDNA in patients with early-stage NSCLC undergoing treatment with curative intent. Methods InVision®MRD is a highly sensitive in vitro diagnostic assay, currently available for research use only (RUO), that can detect the presence of tumor DNA traces in cell-free DNA from plasma samples of cancer patients. InVision®MRD identifies tumor-specific variants from exome sequencing of tumor tissue and tracks them in plasma specimens by multiplex PCR and high-depth next-generation sequencing. We evaluated the detection of ctDNA in plasma samples collected from the LUng cancer - CIrculating tumor DNA (LUCID) study, which collected plasma samples from 100 patients with NSCLC stages I-III who underwent radical treatment with curative intent, either surgery or radiotherapy ± chemotherapy. Of patients in the LUCID study, 60% had stage I NSCLC and 40% patients had stage II/III disease, according to TNM 7th edition. Results To evaluate the InVision®MRD assay, a subset of samples from the LUCID study were analyzed. Samples were collected before and after surgery and chemo-radiotherapy from patients with early-stage NSCLC. Using multiplexed analysis of 48 patient-specific variants and high-depth sequencing, ctDNA was detected in 50% of pre-treatment samples analyzed from the first set of 18 patients, at ctDNA fractions ranging from 20 ppm (equivalent to 0.002%) to 19576 ppm (equivalent to 1.958%). Conclusions These findings highlight an opportunity to improve ctDNA detection for early stage NSCLC using a patient-specific plasma sequencing assay. Initial detection rates have reached 50% for patients with early-stage disease prior to treatment, including detection of ctDNA to levels as low as a few parts per million. Together with further data to be presented, this suggests a possible route to improving treatment for early stage NSCLC by detection of residual disease post treatment and for monitoring for early detection of relapse. Citation Format: Katrin Heider, Davina Gale, Andrea Ruiz-Valdepenas, Giovanni Marsico, Garima Sharma, Malcolm Perry, Robert Osborne, Karen Howarth, Tadd Lazarus, Viona Rundell, Jelena Belic, Jerome Wulff, Susan Harden, Doris M. Rassl, Robert C. Rintoul, Nitzan Rosenfeld. Sensitive detection of ctDNA in early stage non-small cell lung cancer patients with a personalized sequencing assay [abstract]. In: Proceedings of the Annual Meeting of the American Association for Cancer Research 2020; 2020 Apr 27-28 and Jun 22-24. Philadelphia (PA): AACR; Cancer Res 2020;80(16 Suppl):Abstract nr 735.

Considerations for the Surgical Management of Early Stage Lung Cancer During the COVID-19 Pandemic

The highly transmissible novel coronavirus (COVID-19) has infected over 8.8 million people globally and has upended the delivery of health care in the United States, creating unprecedented challenges to providing care to patients with early stage non–small cell lung cancer (NSCLC). The initial surge of patients with COVID-19 that have flooded hospitals has put a strain on physical space, workforce, and supplies. In addition, social distancing and the risk of COVID-19 transmission has created significant barriers for thoracic surgeons to diagnose and treat patients. Many hospitals across the country have temporarily suspended elective operations to preserve hospital beds, ventilators, and personal protective equipment. Currently, the pandemic has greatly disrupted the current standard of resection after adequate staging with imaging and/or surgical staging for early stage NSCLC well beyond the initial acute phase; therefore, a new paradigm for effective management will need to be devised until the COVID-19 pandemic is eradicated with systematic vaccination and herd immunity. Thoracic surgeons will need to recalibrate their approach to ensure that patients receive timely and effective treatment for early stage NSCLC. The management of early stage NSCLC during the COVID-19 pandemic should be balanced with available hospital resources, risk of progression of disease, risk of transmission of COVID-19 to patient and surgeon, and the availability of alternative therapies. This article will address the current challenges with treating early stage NSCLC during the COVID-19 pandemic and provide a clinical framework for providing effective surgical therapy while mitigating the risk of transmission of the SARS-CoV-2 virus to patients and surgeons.

The European experience.

Traditionally, pulmonary lobectomy has always been considered as the gold standard for the treatment of early stage non-small cell lung cancer (NSCLC); limited resections have been proposed in case of “compromised” patients, with relevant comorbidities. In the last years, the interest in anatomical segmentectomies among surgeons has been progressively growing, even for patients fit for lobectomy, in selected cases. In this article we debate the current trends in the treatment of early stage NSCLC around Europe.

Novel treatment strategies for early-stage lung cancer: the oncologist's perspective.

Management of early-stage non-small cell lung cancer (NSCLC) consists in multimodal treatment, including surgery, radiotherapy and chemotherapy. The mainstay of treatment is radical surgery. Definitive radiotherapy using stereotactic techniques can provide adequate local disease control, and is the treatment of choice in medically inoperable patients. Most early-stage patients are at significant risk of disease relapse after local treatment. Adjuvant platinum-based chemotherapy has demonstrated to provide an absolute survival benefit of 5% compared to observation. However, unlike advanced/metastatic disease, little progress has been made in the treatment of early-stage NSCLC over the past decade. In recent years, plenty of research has focused on the optimization of adjuvant and neoadjuvant treatment. Several trials with novel drugs, such as targeted agents and immune-checkpoint inhibitors are currently underway, with preliminary positive results. Customization of treatment on patients’ characteristics before, and major pathological response after therapy, will further improve survival outcomes in this subset of patients.

Impact of Surveillance After Lobectomy for Lung Cancer on Disease Detection and Survival

IntroductionExisting guidelines for surveillance after non–small-cell lung cancer (NSCLC) treatment are inconsistent and have relatively sparse supporting literature. This study characterizes detection rates of metachronous and recurrent disease during surveillance with computed tomography scans after definitive treatment of early stage NSCLC. Materials and MethodsThe incidence of metachronous and recurrent disease in patients who previously underwent complete resection via lobectomy for stage IA NSCLC at a single center from 1996 to 2010 were evaluated. A subgroup analysis was used to compare survival of patients whose initial surveillance scan was 6 ± 3 months (early) versus 12 ± 3 months (late) after lobectomy. ResultsOf 294 eligible patients, 49 (17%) developed recurrent disease (14 local only, 35 distant), and 45 (15%) developed new NSCLC. Recurrent disease was found at a mean of 22 ± 19 months, and new primaries were found at a mean of 52 ± 31 months after lobectomy (P < .01). Five-year survival after diagnosis of recurrent disease was significantly lower than after diagnosis of second primaries (2.3% vs. 57.5%; P < .001). In the subgroup analysis of 187 patients, both disease detection on the initial scan (2% [2/94] vs. 4% [4/93]; P = .44) and 5-year survival (early, 80.8% vs. late, 86.7%; P = .61) were not significantly different between the early (n = 94) and the late (n = 93) groups. ConclusionSurveillance after lobectomy for stage IA NSCLC is useful for identifying both new primary as well as recurrent disease, but waiting to start surveillance until 12 ± 3 months after surgery is unlikely to miss clinically important findings.

Microwave Ablation in Primary Lung Malignancies.

Lung cancer is the leading cause of cancer-related mortality worldwide. Eighty-five percent of cases correspond to non-small cell lung cancer (NSCLC) and pivotal nonsurgical options for early-stage disease include percutaneous ablation and stereotactic body radiation therapy (SBRT). Microwave Ablation (MWA) is a locoregional treatment option that has many advantages over radiofrequency ablation and has been able to overcome the limitations of this technique in the treatment of early-stage NSCLC. In this review article, we highlight the current evidence supporting the use of MWA in patients with early-stage NSCLC and discuss the technical considerations of the procedure, including optimal patient selection and planning strategies, as well as the potential complications and reported outcomes. Finally, we mention future trends involving ablation in NSCLC, including its role in combination with SBRT in central tumors, management of post-SBRT local recurrence, and its potential as an adjuvant treatment option for patients with resistance to systemic therapy or in combination with checkpoint inhibitors.